The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function.
Aged
Blood Glucose
/ drug effects
C-Peptide
/ metabolism
Diabetes Mellitus, Type 2
/ blood
Dose-Response Relationship, Drug
Female
Gliclazide
/ administration & dosage
Glucose
/ metabolism
Glucose Tolerance Test
Glycated Hemoglobin
/ metabolism
Humans
Hypoglycemic Agents
/ administration & dosage
Incretins
/ metabolism
Insulin
/ blood
Insulin Secretion
/ drug effects
Insulin-Secreting Cells
/ drug effects
Male
Middle Aged
Proof of Concept Study
GIP
GLP-1
KATP channel
beta-cell modeling
beta-cell physiology
gliclazide
incretin effect
incretins
sulphonylureas
type 2 diabetes
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
16 06 2021
16 06 2021
Historique:
received:
23
10
2020
pubmed:
12
3
2021
medline:
5
10
2021
entrez:
11
3
2021
Statut:
ppublish
Résumé
Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM. Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration. A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)]. Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia.
Identifiants
pubmed: 33693776
pii: 6162832
doi: 10.1210/clinem/dgab151
pmc: PMC8692237
doi:
Substances chimiques
Blood Glucose
0
C-Peptide
0
Glycated Hemoglobin A
0
Hypoglycemic Agents
0
Incretins
0
Insulin
0
Gliclazide
G4PX8C4HKV
Glucose
IY9XDZ35W2
Banques de données
ClinicalTrials.gov
['NCT03705195']
Types de publication
Evaluation Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2036-2046Subventions
Organisme : Wellcome Trust
ID : 102820/Z/13/Z
Pays : United Kingdom
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
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